The present invention relates to glycosidation of 4,5-Epoxymorphinan-6-ols using Thioglycosides as glycoside donors. This approach is particularly useful for preparation of protected 4,5-Epoxymorphinan-6-xcex2-D-glucuronides of formula [1]
wherein:
position 7 and 8 can be olefin as shown or dihydro adduct;
R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl;
R1 is alkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl;
R2 is alkyl, haloalkyl, aralkyl;
R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl;
R4 is alkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl.
Since it was established that Morphine-6-xcex2-D-glucuronide (M6G) [1a] is not only a metabolite of Morphine [5] but also has greater analgesic activity1, substantial amounts have been required for clinical trials and evaluation. According to recent publications the morphine metabolite M6G is a more effective and longer lasting analgesic drug than Morphine itself and has fewer side effects.2
Unfortunately, morphine is also metabolized to Morphine-3-glucuronide (M3G) [6], a compound which antagonizes the analgesic effect of Morphine. Since M3G is formed in greater abundance than M6G, there is much interest in using the latter, rather than Morphine, as a pain killing drug.3
The traditional approach to glycosidation of 4,5-Epoxymorphinan-6-ols explores haloglycosides as glycoside donors and the Koenings-Knorr procedure for the activation of haloglycosides (Berrang, B. et al., Synthesis, 1997, 1165 and references cited therein). The main drawbacks of this approach are: low stability of haloglycosides, heterogenic reaction media that make industrial scale-up very tedious, with low and unstable yields, use of heavy metals. Another more recent approach, described by F. Sheinmann et al. (U.S. Pat. No. 5,621,087), describes use of trichloroacetimidates as glycoside donors. The main disadvantages of this approach are: the tedious methods for preparation of the starting trichloroacetimidates; relatively low yields in the glycosidation reaction; difficult purification of the desired product from the reaction mixture.
These methods have, therefore, serious drawbacks for producing bulk material to be used as a pharmaceutical drug. A desirable goal, met by the present invention, has been to devise synthetic methods which avoid toxic and/or expensive reagents, and which cleanly produce the desired products, avoiding tedious and expensive purification steps.
Glycosidation of 4,5-Epoxymorphinan-6-ols with Thioglycosides as a glycoside donors is disclosed. The process comprises reacting 4,5-Epoxymorphinan-6-ols and Thioglycosides in the presence of thiophilic promoters under conditions capable of forming 4,5-Epoxymorphinan-6-glycosides. This novel approach was used for preparation of protected 4,5-Epoxymorphinan-6-xcex2-D-glucuronides. The process provides both high stereo-selectivity and high yields.
The present invention relates to the use of Thioglycosides as glycoside donors for glycosidation of 4,5-Epoxymorphinan-6-ols.
This novel approach has several advantages:
Thioglycosides can be prepared according to known methods starting from inexpensive and commercially available raw materials.
Thioglycosides have high thermal and chemical stability.
Reagents used for the Thioglycoside activation are not toxic and not expensive.
Although any 4,5-Epoxymorphinan-6-ols, suitable for this glycosylation, can be used, preferably compounds of formula [3] are used. 
wherein:
position 7 and 8 can be olefin as shown or dihydro adduct;
R3 and R4 are as previously defined
More preferably, said 4,5-Epoxymorphinanes are selected from 3-O-Acylmorphine, 3-O-Acylnormorphine, 3-O-Acylnalbuphine, 3-O-Acylnalorphine, 3-O-Acyldihydromorphine, 3-O-Benzylmorphine, 3-O-Benzyldihydromorphine, N,O3-Dibenzylnormorphine, Codeine, Ethylmorphine, Dihydrocodeine, Pholcodine, 3-O-Alkoxycarbonylmorphine, 3-O-Benzyloxycarbonylmorphine, N,O3-Bis(benzyloxycarbonyl)normorphine.
Although any Thioglyoside may be used, it is preferred that Thioglycosides of formula [2] are used. 
wherein
R, R1 and R2 are as previously defined
R5 is alkyl or aryl.
More preferably the Thioglycosides of the present invention are selected from the compounds of formula [12]. 
wherein
R, R2 and R5 are as previously defined;
Most preferably Thioglycosides of formula [11] are used. 
wherein
R and R5 are as previously defined.
Thiophilic promoters used in said glycosidation could be selected from halonium ion source, Dimethyl(methylthio)sulfonium triflate or tetrafluoroborate, Methyl triflate or fluorosulfonate.
The Halonium ion source used in the present invention is a mixture of N-Halosuccinimide and acid, or lodonium dicollidine perchlorate (IDCP). The said N-Halosuccinimide is preferably selected from N-Iodosuccinimide (NIS) or N-Bromosuccinimide (NBS).
The said acids may be selected from triflic acid, trimethylsilyl triflate, silver triflate or tetrafluoroborate or trifluoromethanesulfonic acid.
Most preferably the said thiophilic promoters are a mixture of NIS and triflic acid, or Dimethyl(methylthio)sulfonium triflate.
Preferably the said reaction occurs in the presence of reaction-inert solvents.
Any reaction-inert solvent may be used. As used above and elsewhere herein, the expression xe2x80x9creaction-inert solventxe2x80x9d refers to a solvent which does not react or decompose with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. In general, the solvent can comprise a single entity, or contain multiple components.
Preferably the said reaction-inert solvents are non-protic and are selected from Dichloromethane, Chloroform, 1,2-Dichloroethane, Ether, Acetonitrile, or mixture thereof. Diethyl ether or ethyl acetate may alternatively or additionally be used as a non-protic reaction-inert solvent. Dichloromethane is an especially preferred solvent.
It may be also preferred to conduct the said coupling reaction in the presence of additives to buffer or to activate the thiophilic promoter. The above additives may be selected from molecular sieves, tertiary amines, tetraalkylureas, organic and inorganic acids and salts.
Preferably about 1 equivalent to about 2 equivalents of the Thioglycoside is used. It is specially preferred that about 1 equivalent to about 1.5 equivalents of Thioglycoside is used. The said 4,5-Epoxymorphinanes may be used as an individual compounds or alternatively as corresponding salts thereof or complexes.
Any environment or conditions (e.g. temperature, time, solvent) suitable for the glycosidation reaction may be used. However, it is preferred that the reaction occurs at a temperature of about xe2x88x9250xc2x0 C. to about 100xc2x0 C. and preferably from about xe2x88x9220xc2x0 C. to 20xc2x0 C. This reaction is conveniently carried out at about 0.5 to about 3 atmospheres.
This invention makes a significant advance in the chemistry of 4,5-Epoxymorphinan-6-ols by providing an efficient method for preparation of a large number of known and new 4,5-Epoxymorphinan-6-glycosides.
Particularly, protected 4,5-Epoxymorphinan-6-xcex2-D-glucuronides [1] could be obtained by glycosidation of 4,5-Epoxymorphinan-6-ols of formula [3] or salts thereof or complexes containing thereof 
wherein:
position 7 and 8 can be olefin as shown or dihydro adduct;
R3 and R4 are as previously defined.
with thioglycoside of the formula [2]
wherein
R, R1, R2 and R5 are as previously defined.
under conditions capable of forming said protected 4,5-Epoxymorphinan-6-xcex2-D-glucuronides [1] or salts thereof or complexes containing thereof
More preferably, protected N-Methy-4,5-epoxymorphinan-6-xcex2-D-glucuronides of formula [4] or salts thereof or complexes containing thereof could be obtained by glycosidation of N-Methyl-4,5-epoxymorphinan-6-ol of formula [3a] with Thioglycosides of formula [12]
wherein
R, R2, R5 and R7 are as previously defined.
Said protected N-Methyl-4,5-epoxymorphinan-6-xcex2-D-glucuronide of formula [4] could be important intermediates for the synthesis of Morphine-6-xcex2-D-glucuronide (M6G).
It should be understood that the invention is not limited to the particular embodiments shown and described herein, but that various changes and modifications may be made without departing from the spirit and scope of this novel concept as defined by the following claims.